Kaposi's sarcoma- and B cell lymphoma-associated human herpesvirus 8 (HHV-8) specifies particular proteins that are believed to contribute to angioproliferative and malignant pathogenesis. Key among these is the interleukin-6 homologue, vIL-6, which via its signal transducing properties promotes angiogenesis, cell proliferation and cell survival. The expression of vIL-6 is maximal during lytic, productive replication, but we have demonstrated that it is also expressed as a bone fide latent protein in primary effusion lymphoma (PEL) cells, and, coupled with its predominant intracellular localization, acts in an autocrine manner via ER-initiated intracellular signaling to support PEL growth and survival. Other latency functions of vIL-6, mediated from the ER compartment, may be operative. Unpublished data from this laboratory have established that depletion of latently expressed vIL-6 in PEL cells leads to increased RTA expression and to lytic reactivation, suggesting a role of vIL-6 in regulation of latent-lytic switching. During chemically-induced lytic reactivation, we have found that vIL-6 is a negative regulator of virus production in both endothelial and PEL cells. The present application will focus on the molecular basis of vIL-6 retention and signaling within the ER compartment and the mechanisms and roles of vIL-6 function in relation to virus biology, in part by utilizing the unique reagents and knowledge that we have acquired from our previous studies of vIL-6. The three aims will examine: (1) the roles of ER proteins calnexin and VKORC1 in vIL-6 localization and activity;(2) ER-localized signaling and functions of vIL-6;(3) the role of vIL-6 in the regulation of latent-lytic switching and productive replication. These areas of study are novel and, we believe, of considerable value to future development of anti-viral and therapeutic strategies.

Public Health Relevance

Human herpesvirus 8 (HHV-8) is linked etiologically with endothelial and B cell malignancies and encodes a cytokine homologue, referred to as viral interleukin-6 (vIL-6), which is believed to contribute to disease development, but its role in virus biology is unknown. Our own data have revealed that vIL-6 is essential for growth and survival of cells latently infected with HHV-8 and that it regulates the switch to productive replication and efficiency of virus production. The goal of the proposed research is to characterize the major mechanisms by which vIL-6 functions in these processes, research that will have direct relevance to the development of novel anti-viral strategies that could lead to effective prevention and treatment of HHV-8- associated diseases.

National Institute of Health (NIH)
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AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
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Read-Connole, Elizabeth Lee
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Johns Hopkins University
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Cousins, Emily; Gao, Yang; Sandford, Gordon et al. (2014) Human herpesvirus 8 viral interleukin-6 signaling through gp130 promotes virus replication in primary effusion lymphoma and endothelial cells. J Virol 88:12167-72
Cousins, Emily; Nicholas, John (2014) Molecular biology of human herpesvirus 8: novel functions and virus-host interactions implicated in viral pathogenesis and replication. Recent Results Cancer Res 193:227-68
Chen, Daming; Gao, Yang; Nicholas, John (2014) Human herpesvirus 8 interleukin-6 contributes to primary effusion lymphoma cell viability via suppression of proapoptotic cathepsin D, a cointeraction partner of vitamin K epoxide reductase complex subunit 1 variant 2. J Virol 88:1025-38
Cousins, Emily; Nicholas, John (2013) Role of human herpesvirus 8 interleukin-6-activated gp130 signal transducer in primary effusion lymphoma cell growth and viability. J Virol 87:10816-27
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Boulanger, Martin J; Chow, Dar-chone; Brevnova, Elena et al. (2004) Molecular mechanisms for viral mimicry of a human cytokine: activation of gp130 by HHV-8 interleukin-6. J Mol Biol 335:641-54
Li, H; Wang, H; Nicholas, J (2001) Detection of direct binding of human herpesvirus 8-encoded interleukin-6 (vIL-6) to both gp130 and IL-6 receptor (IL-6R) and identification of amino acid residues of vIL-6 important for IL-6R-dependent and -independent signaling. J Virol 75:3325-34

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